KR20190042940A - Pharmaceutical Composition for Preventing or Treating cancer comprising BIETPC as Active Ingredients - Google Patents

Pharmaceutical Composition for Preventing or Treating cancer comprising BIETPC as Active Ingredients Download PDF

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KR20190042940A
KR20190042940A KR1020170134626A KR20170134626A KR20190042940A KR 20190042940 A KR20190042940 A KR 20190042940A KR 1020170134626 A KR1020170134626 A KR 1020170134626A KR 20170134626 A KR20170134626 A KR 20170134626A KR 20190042940 A KR20190042940 A KR 20190042940A
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glioblastoma
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박채화
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성균관대학교산학협력단
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
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Abstract

The present invention relates to a pharmaceutical composition for preventing or treating cancer and, more specifically, to a pharmaceutical composition for preventing or treating cancer, containing BIETPC (N-[2-(1H-benzimidazol-2-yl)ethyl]-2-thiophenecarboxamide), which is a substance for inhibiting activation of signal transducer and activator of transcription 3 (STAT3), and inhibiting tumor formation and metastasis of glioblastoma. The composition of the present invention selectively inhibits the activation of STAT3 in temozolomide resistant glioblastoma and tumor formation of glioblastoma, thereby degrading metastasis of brain cancer cells and weakening resistance to temozolomide drugs. Thus, the composition of the present invention can be useful for prevention or treatment of cancer through an effect of inhibiting occurrence and recurrence of glioblastoma, and particularly, since the composition is capable of increasing sensitivity of glioma which is resistant to temozolomide known as the only therapeutic agent of brain cancer, the composition is expected to be used as a cancer complex therapeutic agent from now on.

Description

BIETPC를 유효성분으로 포함하는 암 예방 또는 치료용 약학적 조성물 {Pharmaceutical Composition for Preventing or Treating cancer comprising BIETPC as Active Ingredients}[0001] The present invention relates to a pharmaceutical composition for preventing or treating cancer comprising BIETPC as an active ingredient,

본 발명은 BIETPC (N-[2-(1H-benzimidazol-2-yl)ethyl]-2-thiophenecarboxamide)를 유효성분으로 포함하는 암 예방 또는 치료용 약학적 조성물에 관한 것이다. The present invention relates to a pharmaceutical composition for preventing or treating cancer comprising BIETPC (N- [2- (1H-benzimidazol-2-yl) ethyl] -2-thiophenecarboxamide as an active ingredient.

세포질에 존재하는 cytosolic STAT3(signal transducer and activator of transcription 3) 단백질은 활성화된 수용체로 이동하여 인산화효소에 의해 티로신 잔기(Tyr705)가 인산화되어 활성화된다. 활성화된 STAT3는 호모다이머(homodimer) 또는 헤테로다이머(heterodimer)를 형성한 후, 핵으로 이동하여 세포 증식(cell proliferation), 형질전환(transformation), 및 세포사멸(apoptosis)과 관련된 유전자들의 전사를 조절한다. 최근 이처럼 전사인자로 활성화된 STATs가 많은 암세포와 암 조직에서 관찰된다고 보고되고 있으며, 이중 STAT3는 가장 활성화된 전사인자로 알려져 있다. The cytosolic STAT3 (signal transducer and activator of transcription 3) protein in the cytoplasm migrates to the activated receptor and is activated by phosphorylation of the tyrosine residue (Tyr705) by the phosphorylation enzyme. Activated STAT3 forms a homodimer or heterodimer and then migrates to the nucleus to regulate the transcription of genes involved in cell proliferation, transformation, and apoptosis do. Recently, STATs activated by transcription factors have been reported to be observed in many cancer cells and cancer tissues, and STAT3 is known to be the most active transcription factor.

한편, 교모세포종(Glioblastoma) 또는 다형성아교모세포종(Glioblastoma multiforme; GBM)은 뇌종양의 약 12~15%를 차지하는 가장 일반적인 악성 뇌암으로, WHO(World Health Organization)의 암 악성도에 따른 Ⅰ~ Ⅳ의 등급 시스템에서 교모세포종은 성장속도가 매우 빠르고 위험한 잠재력을 지닌 가장 악성도가 높은 종양으로서 Ⅳ 등급으로 분류된다.  Glioblastoma or glioblastoma multiforme (GBM) is the most common malignant brain cancer, accounting for approximately 12-15% of brain tumors. It is classified as a grade I to IV according to WHO (World Health Organization) In the system, glioblastomas are the most malignant tumors with a very rapid growth rate and dangerous potential and are classified as grade IV.

교모세포종은 티로신 인산화효소 수용체(receptor tyrosine kinase; RTK) 신호전달 경로가 비정상적으로 활성화되는 특성을 보이며, 계속적으로 활성화된 STAT3(signal transducer and activator of transcription 3)가 높은 등급의 신경교종에서 EGFR(epidermal growth factor receptor)과 함께 발현한다고 보고되어 있다. 또한 STAT3의 활성화가 교모세포종 암줄기세포의 생존유지에 매우 중요하다고 알려져 있으며, EGFR은 STAT3의 이동을 위한 골격을 제공하며, 인산화에 의해 활성화된 STAT3는 엔도좀상의 수용체-리간드와 공존하고 세포막에서 핵 주변으로 이동한다고 보고되고 있다. The glioblastoma is characterized by abnormal activation of the receptor tyrosine kinase (RTK) signaling pathway, and the continuously activated STAT3 (signal transducer and activator of transcription 3) growth factor receptor). In addition, activation of STAT3 is known to be crucial for the survival of glioblastoma stem cells. EGFR provides the framework for STAT3 transfer, and STAT3 activated by phosphorylation coexists with the receptor-ligand on endosomes, It is reported to move around.

현재 악성 뇌암인 교모세포종의 치료법으로는 테모졸로마이드(Temozolomide)가 유일한 경구용 항암제로 알려졌으나, 대부분의 환자에서 약물에 대한 내성이 일어나며 내성이 일어난 후에는 더 이상 치료 방안이 없다는 문제점이 있어, 이에, 테모졸로마이드 내성 교모세포종에 대한 치료제 개발을 위한 연구가 계속 이루어지고 있다. Currently, Temozolomide is known to be the only oral anticancer drug for the treatment of glioblastoma, a malignant brain cancer. However, most patients have resistance to drugs and no treatment after tolerance, Therefore, studies for the development of therapeutic agents for the temozolomide resistant glioblastoma are continuing.

한국등록특허 제10-1664663호Korean Patent No. 10-1664663

본 발명자들은 BIETPC (N-[2-(1H-benzimidazol-2-yl)ethyl]-2-thiophenecarboxamide)가 테모졸로마이드 내성 교모세포종에서 STAT3의 활성화 및 교모세포종의 종양형성 및 전이능력을 억제한다는 것을 확인하고, 이에 기초하여 본 발명을 완성하였다. We have found that BIETPC (N- [2- (1H-benzimidazol-2-yl) ethyl] -2-thiophenecarboxamide inhibits the activation of STAT3 and tumorigenic and metastatic potential of glioblastomas in temozolomide resistant glioblastoma The present invention has been completed on the basis thereof.

이에, 본 발명은 BIETPC를 유효성분으로 포함하는 암 예방 또는 치료용 약학적 조성물을 제공하는 것을 목적으로 한다. Accordingly, it is an object of the present invention to provide a pharmaceutical composition for preventing or treating cancer comprising BIETPC as an active ingredient.

그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other matters not mentioned can be clearly understood by those skilled in the art from the following description.

상기와 같은 본 발명의 목적을 달성하기 위하여, 본 발명은 BIETPC (N-[2-(1H-benzimidazol-2-yl)ethyl]-2-thiophenecarboxamide)를 유효성분으로 포함하는, 암 예방 또는 치료용 약학적 조성물을 제공한다. In order to achieve the object of the present invention, the present invention provides a pharmaceutical composition for preventing or treating cancer, which comprises BIETPC (N- [2- (1H-benzimidazol-2-yl) ethyl] -2-thiophenecarboxamide A pharmaceutical composition is provided.

본 발명의 일 구현예로, 상기 암은 뇌암, 뇌종양, 양성성상세포종, 악성성상세포종, 뇌하수체 선종, 뇌수막종, 뇌림프종, 핍지교종, 두개내인종, 상의세포종, 뇌간종양, 두경부 종양, 후두암, 구인두암, 비강암, 부비동암, 비인두암, 침샘암, 하인두암, 갑상선암, 흉부종양, 소세포성 폐암, 비소세포성 폐암, 흉선암, 종격동 종양, 식도암, 유방암, 남성유방암, 복부종양, 위암, 간암, 담낭암, 담도암, 췌장암, 소장암, 대장암, 항문암, 방광암, 신장암, 남성생식기종양, 음경암, 요도암, 전립선암, 여성생식기종양, 자궁경부암, 자궁내막암, 난소암, 자궁육종, 질암, 여성외부생식기암, 여성요도암, 피부암, 골수종, 백혈병 및 악성림프종으로 이루어진 군으로부터 선택된 1종 이상인 것을 특징으로 한다. In one embodiment of the present invention, the cancer is selected from the group consisting of brain cancer, brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, brain lymphoma, oligodendroglioma, intracranial lesion, epidermoid tumor, brain tumor, head and neck tumor, Nasopharyngeal carcinoma, mediastinal tumor, esophageal cancer, breast cancer, male breast cancer, abdominal tumor, gastric cancer, hepatic cancer, gallbladder cancer, nasopharyngeal cancer, nasopharyngeal cancer, nasal cancer, sinus cancer, nasopharyngeal cancer, salivary gland cancer, hypopharyngeal cancer, thyroid cancer, Cancer of the uterus, endometrial cancer, ovarian cancer, uterine sarcoma, endometrial cancer, endometrial cancer, endometrial cancer, endometrial cancer, endometrial cancer, Vaginal cancer, female gonadal cancer, female urethral cancer, skin cancer, myeloma, leukemia, and malignant lymphoma.

본 발명의 다른 구현예로, 상기 뇌암은 테모졸로마이드 내성 뇌암인 것을 특징으로 한다. In another embodiment of the present invention, the brain cancer is characterized by being temozolomide-resistant brain cancer.

본 발명의 또 다른 구현예로, 상기 조성물은 STAT3 (signal transducer and activator of transcription 3)의 활성을 억제하는 것을 특징으로 한다. In another embodiment of the present invention, the composition is characterized by inhibiting the activity of STAT3 (signal transducer and activator of transcription 3).

본 발명의 또 다른 구현예로, 상기 조성물은 교모세포종의 종양형성 또는 전이능력을 억제하는 것을 특징으로 한다. In another embodiment of the present invention, the composition is characterized by inhibiting tumorigenic or metastatic ability of a glioblastoma.

본 발명의 또 다른 구현예로, 상기 조성물은 약리학적으로 허용 가능한 담체(carrier) 또는 보조제(additive)를 더 함유할 수 있다. In another embodiment of the present invention, the composition may further contain a pharmacologically acceptable carrier or additive.

또한, 본 발명은 BIETPC (N-[2-(1H-benzimidazol-2-yl)ethyl]-2-thiophenecarboxamide)를 유효성분으로 포함하는 약학적 조성물을 개체에 투여하는 단계를 포함하는, 암 예방 또는 치료 방법을 제공한다.The present invention also relates to a method for preventing or treating cancer, comprising administering to a subject a pharmaceutical composition comprising BIETPC (N- [2- (1H-benzimidazol-2-yl) ethyl] -2-thiophenecarboxamide as an active ingredient. Provide a treatment method.

나아가, 본 발명은 BIETPC (N-[2-(1H-benzimidazol-2-yl)ethyl]-2-thiophenecarboxamide)의 암 예방 또는 치료 용도를 제공한다. Furthermore, the present invention provides the use of BIETPC (N- [2- (1H-benzimidazol-2-yl) ethyl] -2-thiophenecarboxamide for cancer prevention or treatment.

본 발명의 BIETPC (N-[2-(1H-benzimidazol-2-yl)ethyl]-2-thiophenecarboxamide)는 테모졸로마이드 내성 교모세포종에서 STAT3의 활성화를 억제하며, 교모세포종의 종양형성 및 전이능력을 억제함으로써, 뇌암 세포의 전이 능력을 저해시키며, 테모졸로마이드 약물에 대한 내성을 약화시키는데 효과적이다. 이와 같은 교모세포종 발병 및 재발 억제효과를 통하여 암의 예방 또는 치료에 유용하게 이용할 수 있을 뿐만 아니라, 특히, 뇌암의 유일한 치료제로 알려진 테모졸로마이드에 내성을 보이는 신경교종의 민감성을 증가시킬 수 있으므로, 향후 암 복합치료제로서 유용하게 사용될 수 있을 것으로 기대된다.The present BIETPC (N- [2- (1H-benzimidazol-2-yl) ethyl] -2-thiophenecarboxamide inhibits the activation of STAT3 in temozolomide resistant glioblastomas and inhibits tumorigenic and metastatic ability of glioblastoma Inhibiting the metastatic ability of brain cancer cells and is effective in weakening the resistance to the temozolomide drug. In addition to being useful for the prevention or treatment of cancer through the effect of inhibiting the onset of glioblastoma and recurrence, it is possible to increase the sensitivity of gliomas resistant to temozolomide, which is known as the sole treatment for brain cancer, It is expected to be useful as a combination therapy for cancer in the future.

도 1은 BIETPC (N-[2-(1H-benzimidazol-2-yl)ethyl]-2-thiophenecarboxamide)의 화학적 구조를 나타낸 것이다.
도 2는 테모졸로마이드 내성 교모세포종 세포(LN229-TMZR)들을 모체 세포(LN229)와 비교하였을 때 테모졸로마이드에 강한 내성을 갖고 있음을 확인한 결과를 나타낸 것이다.
도 3은 테모졸로마이드 내성 교모세포종 세포(LN229-TMZR)와 대조군인 모체 세포(LN229)를 비교하였을때, LN229-TMZR 세포의 STAT3 활성이 상대적으로 높으며, BIETPC의 처리로, STAT3 활성이 감소되었음을 확인한 결과를 나타낸 것이다.
도 4는 BIETPC를 처리하였을 때, 대조군인 모체 세포(LN229)에는 영향을 미치지 않으나, 테모졸로마이드 내성 교모세포종 세포(LN229-TMZR)에서는 이로 인하여 스피어(sphere) 형성이 감소되었음을 확인한 결과를 나타낸 것이다.
도 5는 테모졸로마이드 내성 교모세포종 세포(LN229-TMZR)의 경우 BIETPC의 억제중간값(median inhibitory concentration; IC50)이 0.94μmol/L으로 낮은 반면, 대조군인 모체 세포(LN229)는 상대적으로 높다는 사실을 확인한 결과를 나타낸 것이다.
도 6a 및 도 6b는 BIETPC를 처리하였을 때, 테모졸로마이드 내성 교모세포종 세포(LN229-TMZR)는 시간이 지나면서 세포성장이 감소하였지만, 이에 반하여 정상 뇌세포인 별 아교 세포(astrocyte)는 세포성장에 영향을 받지 않았음을 확인한 결과를 나타낸 것이다. Figure 1 shows the chemical structure of BIETPC (N- [2- (1H-benzimidazol-2-yl) ethyl] -2-thiophenecarboxamide.
Fig. 2 shows the results of confirming that temozolomide resistant glioblastoma cells (LN229-TMZR) are resistant to temozolomide when compared to maternal cells (LN229).
FIG. 3 shows that the STAT3 activity of LN229-TMZR cells was relatively high and the STAT3 activity was decreased by treatment with BIETPC when compared with the temozolomide resistant glioma cells (LN229-TMZR) and the control cell (LN229) The results are as follows.
FIG. 4 shows that while the BIETPC treatment did not affect the parental cell (LN229), it was confirmed that the formation of sphere was reduced in the temozolomide resistant glioblastoma cell line (LN229-TMZR) .
FIG. 5 shows that the median inhibitory concentration (IC50) of BIETPC was low at 0.94 μmol / L in the case of the temozolomide resistant glioblastoma cell line (LN229-TMZR), while the maternal cell (LN229) As shown in FIG.
6A and 6B show that when the BIETPC was treated, the cell growth of the temozolomide resistant glioblastoma cell line (LN229-TMZR) decreased over time, whereas the astrocyte, the normal brain cell, The results are shown in Fig.

본 발명자들은 테모졸로마이드 내성 교모세포종에 대한 치료제 개발을 위하여 연구 노력한 결과, BIETPC(N-[2-(1H-benzimidazol-2-yl)ethyl]-2-thiophenecarboxamide)가 테모졸로마이드 내성 교모세포종에서 STAT3의 활성화를 억제하며, 교모세포종의 종양형성 및 전이능력을 억제한다는 것을 확인하고, 이에 기초하여 본 발명을 완성하였다.The inventors of the present invention have found that when BIETPC (N- [2- (1H-benzimidazol-2-yl) ethyl] -2-thiophenecarboxamide is administered in a temozolomide resistant glioblastoma Inhibits the activation of STAT3 and inhibits the tumorigenic and metastatic ability of the glioblastoma. Based on this finding, the present invention has been completed.

이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.

본 발명은 BIETPC (N-[2-(1H-benzimidazol-2-yl)ethyl]-2-thiophenecarboxamide)를 유효성분으로 포함하는 암 예방 또는 치료용 약학적 조성물을 제공한다. The present invention provides a pharmaceutical composition for preventing or treating cancer comprising BIETPC (N- [2- (1H-benzimidazol-2-yl) ethyl] -2-thiophenecarboxamide as an active ingredient.

본 발명에서 사용되는 용어 "암"이란 조직 내에서 질서를 무시하고 무제한 증식하는 미분화 세포로 구성된 종괴(腫塊), 또는 종양을 형성하는 병으로, 궁극적으로는 주위의 정상조직이나 기관을 침윤하여 파괴시키고 원발병소(原發病巢)에서 개체의 어떤 기관이든 전이하여 새로운 성장 장소를 만들 수 있어 개체의 생명을 빼앗아 갈 수 있는 질환군을 총칭한다. As used herein, the term " cancer " refers to a mass consisting of undifferentiated cells that undergoes an unlimited proliferation in the tissue, or a tumor that forms a tumor, and ultimately destroys the tumor by invading surrounding normal tissues or organs It is collectively referred to as a group of diseases that can take away the life of an individual by transferring any organ of an individual from a primary lesion (原 发 病 巢) to a new growth place.

본 발명에서 사용되는 용어 "뇌암"이란 뇌 속에서 세포가 정상적인 성장 한계를 무시하고 분열 및 성장하는 공격적(aggressive) 특성, 주위 조직에 침투하는 침투적(invasive) 특성 및 체내의 다른 부위로 퍼지는 전이적(metastatic) 특성을 갖는 세포에 의한 질병을 총칭하는 의미이다. 본 명세서에서 상기 뇌암은 악성 종양(malignant tumor)과 동일한 의미로도 사용된다. As used herein, the term " brain cancer " refers to an aggressive characteristic of a cell in the brain that disregards normal growth limits and divides and grows, invasive characteristics that penetrate surrounding tissues, It is a generic term for diseases caused by cells with metastatic characteristics. In this specification, brain cancer is also used in the same sense as malignant tumor.

본 발명에서 사용되는 용어, "예방"이란 본 발명에 따른 약학적 조성물의 투여에 의해 뇌암을 억제시키거나 발병을 지연시키는 모든 행위를 의미한다. As used herein, the term " prophylactic " means any action that inhibits or delays the onset of brain cancer by the administration of the pharmaceutical composition according to the present invention.

본 발명에서 사용되는 용어, "치료"란 본 발명에 따른 약학적 조성물의 투여에 의해 뇌암에 의한 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.As used herein, the term " treatment " means any action that improves or alters the symptoms of brain cancer by administration of the pharmaceutical composition according to the present invention.

본 발명의 상기 암은 뇌암, 뇌종양, 양성성상세포종, 악성성상세포종, 뇌하수체 선종, 뇌수막종, 뇌림프종, 핍지교종, 두개내인종, 상의세포종, 뇌간종양, 두경부 종양, 후두암, 구인두암, 비강암, 부비동암, 비인두암, 침샘암, 하인두암, 갑상선암, 흉부종양, 소세포성 폐암, 비소세포성 폐암, 흉선암, 종격동 종양, 식도암, 유방암, 남성유방암, 복부종양, 위암, 간암, 담낭암, 담도암, 췌장암, 소장암, 대장암, 항문암, 방광암, 신장암, 남성생식기종양, 음경암, 요도암, 전립선암, 여성생식기종양, 자궁경부암, 자궁내막암, 난소암, 자궁육종, 질암, 여성외부생식기암, 여성요도암, 피부암, 골수종, 백혈병 및 악성림프종으로 이루어진 군으로부터 선택된 1종 이상일 수 있고, 바람직하게는 뇌암이며, 보다 바람직하게는 테모졸로마이드 내성 뇌암일 수 있으나, 이에 제한되는 것은 아니다. The cancer of the present invention may be used in the treatment of brain cancer, brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, brain lymphoma, oliguria, intracranial lesion, epidermoid tumor, brainstem tumor, head and neck tumor, laryngeal cancer, Cancer, breast cancer, male breast cancer, abdominal tumor, gastric cancer, liver cancer, gallbladder cancer, biliary cancer, pancreatic cancer, cancer of the liver, cancer of the liver, nasopharyngeal cancer, salivary gland cancer, hypopharynx, thyroid cancer, chest tumor, small cell lung cancer, Cancer of the uterus, endometrial cancer, ovarian cancer, uterine sarcoma, vaginal cancer, female reproductive organs, uterine cancer, prostate cancer, female germ cell tumor, Cancer, cancer of the female urethra, skin cancer, myeloma, leukemia and malignant lymphoma, preferably brain cancer, more preferably temozolomide-resistant brain cancer, It is not to be limited to.

본 발명의 상기 조성물은 STAT3(signal transducer and activator of transcription 3) 활성을 억제할 뿐만 아니라, 교모세포종의 종양형성 또는 전이능력을 억제하는 것을 특징으로 한다. The composition of the present invention is characterized not only in inhibiting STAT3 (signal transducer and activator of transcription 3) activity, but also inhibiting tumorigenic or metastatic ability of glioblastoma.

본 발명에서, "활성을 억제"하는 것이란 표적 유전자 또는 표적 단백질의 기능 저하를 야기하는 것을 의미한다.In the present invention, " inhibiting activity " means that the function of the target gene or the target protein is degraded.

본 발명에서, "교모세포종"이란 뇌의 교세포에서 발생한 종양 중 조직학적으로 핵의 비정형성, 유사분열상, 혈관내피세포의 증식, 괴사가 관찰되는 악성도가 가장 높은 종양을 의미한다.In the present invention, " glioblastoma " refers to a tumor with the highest degree of malignancy in which tumor necrosis, mitosis, vascular endothelial cell proliferation and necrosis are observed histologically in a tumor of the brain.

본 발명의 실시예에서는, 테모졸로마이드 내성 교모세포종 세포(LN229-TMZR)와 모체 세포(LN229)를 비교하였을 때, LN229-TMZR 세포가 상대적으로 테모졸로마이드에 강한 내성을 갖고 있음을 확인하였으며(실시예 2 참조),In the examples of the present invention, it was confirmed that LN229-TMZR cells were relatively resistant to temozolomide when compared to the temozolomide resistant glioblastoma cell line (LN229-TMZR) and the maternal cell line (LN229 See Example 2),

본 발명의 다른 실시예에서는, 테모졸로마이드 내성 교모세포종 세포에 미치는 BIETPC (N-[2-(1H-benzimidazol-2-yl)ethyl]-2-thiophenecarboxamide)의 효과를 확인하기 위하여 테모졸로마이드 내성 교모세포종 세포(LN229-TMZR)와 모체 세포(LN229)에 BIETPC를 처리하였을 때, STAT3의 활성 및 스피어(sphere)의 형성이 유의적으로 감소하였음을 확인하였다(실시예 3 참조).In another embodiment of the present invention, in order to confirm the effect of BIETPC (N- [2- (1H-benzimidazol-2-yl) ethyl] -2-thiophenecarboxamide on temozolomide resistant glioblastoma cells, It was confirmed that the activity of STAT3 and the formation of spheres were significantly reduced when BIETPC was treated with the glioma cells (LN229-TMZR) and the maternal cells (LN229) (see Example 3).

따라서 상기 결과들로 비추어 볼 때, 본 발명에 따른 BIETPC(N-[2-(1H-benzimidazol-2-yl)ethyl]-2-thiophenecarboxamide)를 유효성분으로 포함하는 약학적 조성물은 암의 예방 또는 치료에 유용한 의약품으로 사용될 수 있다.Accordingly, the pharmaceutical composition comprising BIETPC (N- [2- (1H-benzimidazol-2-yl) ethyl] -2-thiophenecarboxamide according to the present invention as an active ingredient can prevent or prevent cancer It can be used as a medicament useful for treatment.

본 발명에 따른 약학적 조성물은 유효성분 이외에 약제학적으로 허용되는 담체를 포함할 수 있다. 이때, 약제학적으로 허용되는 담체는 제제 시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세 결정성셀룰로스, 폴리비닐피로리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필 히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일 등을 포함하나, 이에 한정되는 것은 아니다. 또한, 상기성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다.The pharmaceutical composition according to the present invention may contain, in addition to the active ingredient, a pharmaceutically acceptable carrier. Herein, pharmaceutically acceptable carriers are those conventionally used at the time of formulation, and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose But are not limited to, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. Further, in addition to the above components, a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like may be further included.

본 발명의 약학적 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구투여(예를 들어, 정맥 내, 피하, 복강 내 또는 국소에 적용)할 수 있으며, 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 시간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다.The pharmaceutical composition of the present invention may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) depending on the intended method, and the dose may vary depending on the condition and the weight of the patient, The mode of administration, the route of administration, and the time, but may be appropriately selected by those skilled in the art.

본 발명의 약학적 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명에 있어서 "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, the term "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level will depend on the type of disease, severity, The sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of the treatment, factors including co-administered drugs, and other factors well known in the medical arts.

본 발명의 또 다른 양태로서, 본 발명은 BIETPC (N-[2-(1H-benzimidazol-2-yl)ethyl]-2-thiophenecarboxamide)를 유효성분으로 포함하는 약학적 조성물을 개체에 투여하는 단계를 포함하는 암 예방 또는 치료 방법을 제공한다. In another embodiment of the present invention, the present invention provides a method for treating a subject, comprising administering to a subject a pharmaceutical composition comprising BIETPC (N- [2- (1H-benzimidazol-2-yl) ethyl] -2-thiophenecarboxamide as an active ingredient And a method for preventing or treating cancer.

본 발명에서 “개체”란 질병의 치료를 필요로 하는 대상을 의미하고, 보다 구체적으로는 인간 또는 비-인간인 영장류, 생쥐 (mouse), 쥐 (rat), 개, 고양이, 말 및 소 등의 포유류를 의미한다.The term " individual " as used herein refers to a subject in need of treatment for a disease, and more specifically refers to a human or non-human primate, mouse, rat, dog, cat, It means mammals.

이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 하기 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다. Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the following examples.

[실시예][Example]

실시예 1. 실험 준비 및 방법Example 1. Experimental preparation and method

1-1. 세포 배양 준비1-1. Cell culture preparation

인간 교모세포종(glioblastoma) 세포주 LN229는 10% fetal bovine serum, penicillin/streptomycin(Gibco BRL)이 포함된 DMEM 배지에 37℃, 5% CO2 조건 하에서 배양하였다. Human glioblastoma cell line LN229 was cultured in DMEM medium containing 10% fetal bovine serum, penicillin / streptomycin (Gibco BRL) at 37 ° C and 5% CO 2 .

1-2. STAT3 활성분석 1-2. STAT3 activity assay

도 1에 나타낸 바와 같은 화학적 구조를 가지고 있는 BIETPC(N-[2-(1H-benzimidazol-2-yl)ethyl]-2-thiophenecarboxamide)의 STAT3(signal transducer and activator of transcription 3) 활성 억제 효과를 알아보기 위하여, 이중루시퍼라제법(dual luciferase assay)을 사용하여 하기의 실험을 수행하였다. The effect of inhibiting STAT3 (signal transducer and activator of transcription 3) activity of BIETPC (N- [2- (1H-benzimidazol-2-yl) ethyl] -2-thiophenecarboxamide having the chemical structure shown in FIG. To demonstrate, the following experiments were performed using a dual luciferase assay.

뇌암 세포주(LN229)에 STAT3의 활성에 비례하여 반딧불 루시퍼라제(firefly luciferase)의 발현이 증가하는 플라스미드(STAT3 luciferase plasmid)와 STAT3의 활성에 비례하여 레닐라 루시퍼라제(Renilla luciferase)를 발현하는 플라스미드를 동시에 트랜스펙션(transfection)하였다. 상기 플라스미드들이 트랜스펙션(transfection)된 뇌암 세포주들을 16시간 배양하였고, BIETPC는 5 μmol/L로 두 시간동안 처리하였다. 두 시간이 지난 후, 반딧불 루시퍼라제와 레닐라 루시퍼라제에 lysis buffer로 수세하였고, 특이적인 별도의 기질(Beetle luciferin과 coelenterazine)을 순차적으로 첨가한 다음, 이를 측정하였다. 이때, 기질의 분해에 의한 발광 강도는 루미노미터(Luminometer)를 이용하여 측정하였다.A plasmid (STAT3 luciferase plasmid) that increases the expression of firefly luciferase in proportion to the activity of STAT3 in the brain cancer cell line (LN229) and a plasmid that expresses Renilla luciferase in proportion to the activity of STAT3 And transfected simultaneously. Brain cancer cell lines transfected with the plasmids were cultured for 16 hours, and BIETPC was treated with 5 μmol / L for 2 hours. After two hours, the firefly luciferase and lenalla luciferase were washed with lysis buffer, and the specific substrate (Beetle luciferin and coelenterazine) was sequentially added and then measured. At this time, the luminescence intensity due to decomposition of the substrate was measured using a luminometer.

1-3. Sphere forming assay1-3. Sphere forming assay

BIETPC의 처리에 따른 스피어(Sphere)의 형성을 분석하고자, Sphere forming assay를 수행하기 위하여, EGF(20ng/mL; BD science), bFGF(20ng/mL; Invitrogen), 및 N2 supplement(1X; Invitrogen)가 포함된 DMEM/F12(Invotrogen) 배지에 세포를 부유시킨 상태로 배양하였다. 배양 후 5 내지 7일이 지났을 때, 형성된 sphere를 회수하여 추가 실험을 위해 단백질을 추출하거나 Accutase(Invitrogen)으로 분리한 후, 이를 분석하였다. (20 ng / mL; BD science), bFGF (20 ng / mL; Invitrogen), and N2 supplement (1X; Invitrogen) to perform sphere forming assay to analyze the formation of sphere according to the treatment of BIETPC. (Invotrogen) medium containing DMEM / F12 (Invitrogen). After 5 to 7 days of incubation, the sphere formed was recovered and proteins were extracted or assayed for Accutase (Invitrogen) for further experiments.

실시예 2. 테모졸로마이드 내성 교모세포종 세포와 모체세포의 테모졸로마이드에 대한 내성 비교Example 2: Resistance to temozolomide in temozolomide resistant glioblastoma cell and maternal cell

테모졸로마이드 내성 교모세포종 세포(LN229-TMZR)와 모체 세포(LN229)의 테모졸로마이드에 대한 내성을 비교하기 위하여, 상기 실시예 1-1의 방법으로 배양한 LN229 세포를 준비하고, 테모졸로마이드의 억제중간값(median inhibitory concentration; IC50)을 측정하였다.To compare the resistance of temozolomide resistant glioblastoma cells (LN229-TMZR) and maternal cells (LN229) to temozolomide, LN229 cells cultured by the method of Example 1-1 were prepared, and temozolomide The median inhibitory concentration (IC50) was measured.

그 결과, 도 2에 나타낸 바와 같이, LN229-TMZR 세포의 IC50는 300μmol/L 이상이었던 반면, 대조군인 LN229 세포의 IC50는 10μmol/L로 상대적으로 낮았다. 이는 테모졸로마이드 내성 교모세포종 세포가 모체세포와 비교하여 테모졸로마이드에 강한 내성을 갖고 있음을 의미한다. As a result, as shown in Fig. 2, the IC50 of LN229-TMZR cells was higher than 300 μmol / L, whereas the IC50 of control LN229 cells was relatively low, 10 μmol / L. This means that the temozolomide resistant glioblastoma cells are more resistant to temozolomide compared to the maternal cells.

실시예 3. 테모졸로마이드 내성 교모세포종 세포에 미치는 BIETPC의 효과 확인Example 3. Confirmation of effect of BIETPC on temozolomide resistant glioblastoma cells

테모졸로마이드 내성 교모세포종 세포(LN229-TMZR)에서 BIETPC(N-[2-(1H-benzimidazol-2-yl)ethyl]-2-thiophenecarboxamide)가 STAT3의 활성 및 스피어(sphere)의 형성에 미치는 효과를 확인하기 위하여, 상기 실시예 1-2 및 1-3의 방법에 따라, LN229-TMZR 세포주에 BIETPC를 처리한 다음, tumor sphere forming assay를 수행하였다. Effects of BIETPC (N- [2- (1H-benzimidazol-2-yl) ethyl] -2-thiophenecarboxamide on the activity of STAT3 and the formation of sphere in temozolomide resistant glioblastoma cell line (LN229- , LN229-TMZR cell lines were treated with BIETPC and tumor sphere forming assay was performed according to the methods of Examples 1-2 and 1-3.

그 결과, 도 3 및 도 4에 나타낸 바와 같이, BIETPC를 처리하였을 때, LN229-TMZR 세포에서의 STAT3활성은 감소하였으나, LN229 세포의 STAT3 활성은 이에 영향을 받지 않았고(도 3 참조), LN229-TMZR 세포에서 sphere 형성은 현저히 감소한 반면, LN229 세포는 sphere 형성에 영향을 받지 않았다(도 4 참조). As a result, as shown in FIG. 3 and FIG. 4, the STAT3 activity in LN229-TMZR cells decreased when treated with BIETPC, but the STAT3 activity of LN229 cells was not affected (see FIG. 3) Sphere formation was significantly reduced in TMZR cells, whereas LN229 cells were not affected by sphere formation (see FIG. 4).

상기로부터, BIETPC가 테모졸로마이드 내성 교모세포종 세포의 STAT3 활성을 억제하며, 스피어 형성을 감소시켜, 교모세포종의 종양형성 능력을 무력화시키고, 교모세포종의 전이능력도 감소시킨다는 사실을 알 수 있다.From the above it can be seen that BIETPC inhibits the STAT3 activity of the temozolomide resistant glioblastoma cells, reduces spear formation, inactivates the tumorigenic ability of glioblastomas, and reduces the metastatic potential of glioblastoma.

아울러, 도 5에 나타낸 바와 같이, BIETPC의 억제중간값(median inhibitory concentration; IC50)을 측정한 결과, LN229-TMZR 세포의 IC50은 0.496μmol/L으로 낮은 반면, 대조군인 모체 세포(LN229)는 100μmol/L이상으로 상대적으로 높은 값을 보였는바, 이는 낮은 BIETPC 농도에서도 효과적으로 교모세포종의 증식이 억제되는 것을 의미한다. As shown in FIG. 5, the median inhibitory concentration (IC50) of BIETPC was measured. As a result, the IC50 of LN229-TMZR cells was as low as 0.496 μmol / L, while the control cell, LN229, / L, which means that the proliferation of glioblastoma is effectively inhibited even at a low BIETPC concentration.

또한, 도 6a 및 도 6b에 나타낸 바와 같이, BIETPC를 처리하였을 때, 테모졸로마이드 내성 교모세포종 세포(LN229-TMZR)는 시간이 지나면서 세포성장이 감소하였지만(도 6a 참조), 이에 반하여 정상 뇌세포인 별 아교 세포(astrocyte)는 세포성장에 영향을 받지 않았다(도 6b 참조).6A and 6B, when the BIETPC was treated, the cell growth of the temozolomide resistant glioblastoma cell line (LN229-TMZR) decreased over time (see FIG. 6A), whereas the normal brain Cell astrocyte was not affected by cell growth (see FIG. 6b).

상기 진술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다.It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the spirit or scope of the invention. There will be. It is therefore to be understood that the above-described embodiments are illustrative in all aspects and not restrictive.

Claims (6)

BIETPC (N-[2-(1H-benzimidazol-2-yl)ethyl]-2-thiophenecarboxamide)를 유효성분으로 포함하는, 암 예방 또는 치료용 약학적 조성물. A pharmaceutical composition for preventing or treating cancer, comprising BIETPC (N- [2- (1H-benzimidazol-2-yl) ethyl] -2-thiophenecarboxamide as an active ingredient. 제1항에 있어서,
상기 암은 뇌암, 뇌종양, 양성성상세포종, 악성성상세포종, 뇌하수체 선종, 뇌수막종, 뇌림프종, 핍지교종, 두개내인종, 상의세포종, 뇌간종양, 두경부 종양, 후두암, 구인두암, 비강암, 부비동암, 비인두암, 침샘암, 하인두암, 갑상선암, 흉부종양, 소세포성 폐암, 비소세포성 폐암, 흉선암, 종격동 종양, 식도암, 유방암, 남성유방암, 복부종양, 위암, 간암, 담낭암, 담도암, 췌장암, 소장암, 대장암, 항문암, 방광암, 신장암, 남성생식기종양, 음경암, 요도암, 전립선암, 여성생식기종양, 자궁경부암, 자궁내막암, 난소암, 자궁육종, 질암, 여성외부생식기암, 여성요도암, 피부암, 골수종, 백혈병 및 악성림프종으로 이루어진 군으로부터 선택된 1종 이상인 것을 특징으로 하는, 약학적 조성물. The method according to claim 1,
Wherein the cancer is selected from the group consisting of brain cancer, brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, brain lymphoma, oligodendroglioma, intracranial lesion, ependymoma, brainstem tumor, head and neck tumor, laryngeal cancer, Cancer of the breast, cancer of the esophagus, breast cancer, male breast cancer, abdominal tumor, gastric cancer, liver cancer, gallbladder cancer, biliary cancer, pancreatic cancer, small bowel cancer, breast cancer, salivary gland cancer, hypopharynx, thyroid cancer, chest tumor, small cell lung cancer, Cancer of the uterus, ovarian cancer, uterine sarcoma, vaginal cancer, female germ cell cancer, female gynecologic cancer, female gynecologic cancer, female gynecological tumor, cervical cancer, endometrial cancer, female gynecologic cancer, female gynecologic cancer, female gynecologic cancer, Urinary tract cancer, skin cancer, myeloma, leukemia, and malignant lymphoma. 제2항에 있어서,
상기 뇌암은 테모졸로마이드 내성 뇌암인 것을 특징으로 하는, 약학적 조성물. 3. The method of claim 2,
Wherein said brain cancer is a temozolomide-resistant brain cancer. 제1항에 있어서,
상기 조성물은 STAT3(signal transducer and activator of transcription 3)의 활성을 억제하는 것을 특징으로 하는, 약학적 조성물. The method according to claim 1,
Wherein said composition inhibits the activity of STAT3 (signal transducer and activator of transcription 3). 제1항에 있어서,
상기 조성물은 교모세포종의 종양형성 또는 전이능력을 억제하는 것을 특징으로 하는, 약학적 조성물. The method according to claim 1,
Wherein said composition inhibits tumorigenic or metastatic ability of a glioblastoma. 제1항에 있어서,
상기 조성물은 약리학적으로 허용 가능한 담체(carrier) 또는 보조제(additive)를 더 함유하는 것을 특징으로 하는, 약학적 조성물. The method according to claim 1,
Wherein said composition further comprises a pharmacologically acceptable carrier or adjuvant.
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